Structure-based design and synthesis of conformationally constrained derivatives of methyl-piperidinopyrazole (MPP) with estrogen receptor (ER) antagonist activity.

Nuclear Estrogen receptors (ER) are cytoplasmic proteins; translocated to the nucleus to induce transcriptional signals after getting bound to the estrogen hormone. ER activation implicated in cancer cell proliferation of female reproductive organs. Thus, the discovery of ER antagonists is a reliable strategy to combat estrogen-dependent breast cancer. Endometrial carcinoma is one of the complications encountered upon long-term therapy by selective estrogen receptor modulators (SERMs) like Tamoxifen (TMX) and methyl piperidinopyrazole (MPP). Thus, the ER-full antagonist is a solution to improve the safety of this class of therapeutics during the treatment of breast cancer. We selected MPP as a lead structure to design conformationally constrained analogs. Structural rigidification is a proven strategy to transform the SERMs into full antagonists. Accordingly, we synthesized 7-methoxy-3-(4-methoxyphenyl)-4,5-dihydro-2H-benzo[g]indazoles (4), (6a-c),(8-12) along with the biphenolic counterparts(13-19)that are the anticipated active metabolites. The 4-nitrophenyl derivative(4)is with the most balanced profile regardingthe in vivoanti-uterotrophic potential (EC50 = 4.160 µM); and the cytotoxicity assay of the corresponding active metabolite(13)against ER+ breast cancer cell lines (MCF-7 IC50 = 7.200 µM, T-47D IC50 = 11.710 µM). The inconsiderable uterotrophic activities of the elaborated ER-antagonists and weak antiproliferative activity of the compound(13)against ovarian cancer (SKOV-3 IC50 = 29.800 µM) highlighted it as a good start point to elaborate potential ER-full antagonists devoid of endometrial carcinoma. Extending the pendant chain that protrudes from the 2-(4-(substituted)-phenyl) ring of the new benzo-indazoles is recommended for enhancing the potency based on the binding mode of compound(13)in the ligand-binding domain (LBD) of ER.

Cytotoxic T Cell Expression of Leukocyte-Associated Immunoglobulin-Like Receptor-1 (LAIR-1) in Viral Hepatitis C-Mediated Hepatocellular Carcinoma.

Virus-related hepatocellular carcinoma (HCC) pathogenesis involves liver inflammation, therefore, despite successful treatment, hepatitis C virus (HCV) may progress to HCC from initiated liver cirrhosis. Cytotoxic T cells (Tcs) are known to be involved in HCV-related cirrhotic complications and HCC pathogenesis. The inhibitory checkpoint leukocyte-associated immunoglobulin-like receptor-1 (LAIR-1) is expressed on Tcs. Therefore, we aimed to determine whether the Tc expression level of LAIR-1 is associated with HCC progression and to evaluate LAIR-1 expression as a noninvasive biomarker for HCC progression in the context of liver cirrhosis related to HCV genotype 4 (G4) in Egyptian patients' peripheral venous blood liquid biopsy. A total of 64 patients with HCC and 37 patients with liver cirrhosis were enrolled in this case-controlled study, and their LAIR-1 expression on Tc related to the progression of liver cirrhosis was examined and compared to that of the apparently healthy control group (n = 20). LAIR-1 expression was analyzed using flow cytometry. Results: The HCC group had significantly higher LAIR-1 expression on Tc and percentage of Tc positive for LAIR-1 (LAIR-1+Tc%) than the HCV G4-related liver cirrhosis group. LAIR-1+Tc% was correlated with the HCC surrogate tumor marker AFP (r = 0.367, p = 0.001) and insulin resistance and inflammation prognostic ratios/indices. A receiver operating characteristic (ROC) curve revealed that adding LAIR-1+Tc% to AFP can distinguish HCC transformation in the Egyptian patients' cohort. Upregulated LAIR-1 expression on Tc could be a potential screening noninvasive molecular marker for chronic inflammatory HCV G4 related liver cirrhosis. Moreover, LAIR-1 expression on Tc may be one of the players involved in the progression of liver cirrhosis to HCC.

Phaco-UCP; combined phacoemulsification and ultrasound ciliary plasty versus phacoemulsification alone for management of coexisting cataract and open angle glaucoma: a randomized clinical trial.

BACKGROUND: Various surgical techniques have been described, to be combined with cataract surgery in glaucoma patients, aiming for an additional reduction of intraocular pressure (IOP), hence minimizing the burden of anti-glaucoma medication (AGM). Ultrasound ciliary plasty (UCP) is a recent microinvasive glaucoma surgery (MIGS) recommended for primary and refractory glaucoma. This study was conducted to evaluate the safety and efficacy of a new technique; combined phacoemulsification and ultrasound ciliary plasty (Phaco-UCP) as a primary surgical treatment for coexisting cataract and open angle glaucoma. METHODS: A randomized clinical trial, including 61 eyes of 61 patients with visually significant cataract and open angle glaucoma, randomized to either Phaco-UCP (study group; 31 eyes) or phacoemulsification alone (Phaco-alone) (control group; 30 eyes). Primary outcomes included reduction in IOP and/or the number of AGM. Secondary outcomes included visual acuity improvement and complications. Qualified Success was defined as an IOP reduction ≥ 20% from baseline value, with an IOP 6-21 mmHg, with no additional AGM or glaucoma surgery. Failure was defined as either < 20% IOP reduction, despite AGM use, the need of glaucoma surgeries or serious complications. RESULTS: At 18 months postoperatively, Phaco-UCP group had a median IOP reduction of 7 mmHg (Q1, Q3 = 3, 10) compared to 2 mmHg (Q1, Q3 = 2, 3) in Phaco-alone group (P < 0.001). Phaco-UCP group had significantly higher success rate at all time points reaching 67.7% at the last follow-up versus 16.7% only in Phaco-alone group (P< 0.001). The median number of AGM significantly decreased from [3 (Q1, Q3 = 2, 4), 3 (Q1, Q3 = 2,3)] respectively, (P =0.3)] at baseline to [1 (Q1,Q3 = 1, 2), 2 (Q1,Q3 = 2, 2)] respectively, (P < 0.001)] at 18 months postoperatively. No serious intraoperative or postoperative complications were encountered in either group. CONCLUSION: Phaco-UCP is a simple, safe and effective procedure for management of coexisting cataract and open angle glaucoma. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT04430647 ; retrospectively registered. June 12, 2020.

Development and evaluation of a physical activity intervention informed by participatory research- a feasibility study.

BACKGROUND: Despite numerous interventions aiming to improve physical activity in socially disadvantaged populations, physical inactivity remains to be a rising challenge to public health globally, as well as, in Sweden. In an effort to address this challenge, a community-based participatory intervention was developed through active community engagement and implemented in a socially disadvantaged neighborhood in Sweden. The current study aims to present the development and initial evaluation of a participatory research driven physical activity intervention. METHODS: Fifteen participants (11 females and 4 males) aged 17-59 years volunteered to participate in the physical activity intervention program. The intervention program was evaluated using a longitudinal mixed methods design measuring health impact changes over time through focus group discussions and quality of life surveys. Further additional biomedical health parameters such as levels of glycosylated hemoglobin, blood pressure, levels of oxygen saturation and body mass index were monitored before and after the intervention. Focus group data were analyzed using content analysis with an inductive approach. The pre-and post-test scores from the survey-based quality of life domains, as well as the health parameters were compared using non-parametric and parametric statistics. RESULTS: Four themes emerged from the analysis of the focus group discussions including sense of fellowship, striving for inclusion and equity, changing the learner perspective and health beyond illness. The scores for the domains Physical Health, Psychological Health, Social Relationships and Health Satisfaction where significantly higher after participation in the physical activity intervention program compared to the pre-test scores (p < .05)s. There were however, no significant changes in the scores for the environmental domain and overall quality of life after intervention compared to that prior to intervention start. Overall, the biomedical health parameters remained stable within the normal ranges during intervention. CONCLUSION: The focus group discussions and results from the surveys and biomedical measures reveal important findings to understand and further develop the intervention program to promote health equity among citizens in disadvantaged areas. Evaluating the feasibility of such an intervention using multiple approaches contributes to effective implementation of it for larger communities in need.

Aflibercept with adjuvant micropulsed yellow laser versus aflibercept monotherapy in diabetic macular edema.

PURPOSE: To assess the impact of micropulsed laser (MPL) on modifying the number of aflibercept injections when used as an adjuvant therapy in diabetic macular edema (DME). METHODS: A prospective randomized interventional clinical study included patients with DME attending Al Hadi Clinic, Kuwait, during the period from May 2017 to December 2018. Patients were allocated in two groups; group A received aflibercept injections alone and group B received combined aflibercept injections followed by MPL within a week. The primary outcome was the number of Aflibercept injections in each group guided by the change in central macular thickness (CMT). All the patients were followed for 18 months. Secondary outcome measures included best corrected visual acuity (BCVA), contrast sensitivity (CS), and any recorded complications. RESULTS: Fifty-four eyes of 51 patients were included (27 in each group). There was no statistically significant difference between the two groups in baseline characteristics except for the age that was statistically higher in group B (p = 0.001). The number of injections were significantly lower in group B (4.1 ± 1.1) than group A (7.3 ± 1.1) (p < 0.005). At 18th month, there was significant reduction in CMT in both groups (p < 0.005) with no statistical difference between the two groups (p = 0.989). Final BCVA in both groups showed statistically significant improvement (p < 0.005) without statistically significant difference between the two groups (p = 0.082). In both groups, the CS showed significant improvement from baseline (p < 0.005). No ocular or systemic adverse effects were observed in either group. CONCLUSION: Supplemental MPL in eyes with DME may decrease the burden of the aflibercept injection frequency while resulting in comparable anatomical and visual outcomes.

Objective and Subjective Outcome of Clear Lensectomy With Toric IOL Implantation After Corneal Collagen Cross-Linking in Selected Cases of Keratoconus.

AIM: To evaluate the visual and topographic outcomes of a two-stage approach treatment for selected cases of progressive keratoconus (KC); corneal collagen cross-linking (CXL) followed by phacoemulsification with toric intraocular lens (IOL) implantation. METHODS: The study included 9 eyes of 6 patients diagnosed with progressive KC, aged from 35 to 47 years (41.6±11.2 years). All studied eyes underwent a two-stage approach treatment: first corneal collagen CXL followed after at least 6 months by phacoemulsification with foldable toric IOL implantation in both eyes of three patients and only one eye of the other three patients. A complete ophthalmological examination was performed preoperatively and postoperatively. Topographical and visual outcomes were evaluated during 1-year follow-up period. RESULTS: At baseline, seven eyes had mild and two eyes had moderate KC. Sphere ranged from -3.00 to -8.00 diopter (D) and cylinder from -3.50 to -5.50 D. All eyes could be corrected by glasses to 0.50 (log of minimal angle of resolution [logMAR]) or more. At 6 months after CXL, only Kmax decreased significantly from baseline, with no change in visual acuity or manifest refraction. After phacoemulsification with toric IOL implantation, sphere changed from -5.74±1.88 D preoperatively to 0.33±0.72 D 12 months postoperatively (P<0.001), and cylinder changed from -4.53±0.98 to -1.10±0.76 D (P<0.001). There was significant improvement in mean uncorrected distance visual acuity from logMAR 1.43±0.51 preoperatively to 0.30±0.09 postoperatively (P<0.001) and the mean corrected distance visual acuity (CDVA) from 0.34±0.12 preoperatively to 0.24±0.13 (P=0.03) 1 year after IOL implantation. All patients were satisfied with their visual improvement. CONCLUSIONS: This two-stage approach in selected cases of progressive KC is a safe and effective procedure regarding keratometric stability, and visual and refractive results.

Objective and subjective diagnostic parameters in the fellow eye of unilateral keratoconus.

BACKGROUND: Keratoconus (KC) is usually a bilateral corneal ectatic disease. For significant asymmetric presentation (so called unilateral KC), the fellow eye has the mildest and earliest form of the disease, which is typically called forme fruste keratoconus. The aim of this study was to evaluate the sensitivity and specificity of parameters derived from a Scheimpflug imaging system (Pentacam) as well as the changes in the quality of mesopic vision in the apparently normal fellow eye (forme fruste) to detect the earliest and most sensitive parameters. METHODS: Patients with clinical keratoconus in one eye and forme fruste keratoconus in the fellow eye were compared to subjects with normal eyes. The patients were examined using a rotating Scheimpflug imaging system (Pentacam).The following parameters were evaluated: keratometry, minimum corneal thickness, pachymetry progression index (PPI), Ambrósio relational thickness (ART), posterior elevation, back difference elevation (BDE) and multimetric D index(D index). Receiver operating characteristic (ROC) curves were analyzed by evaluating the area under the curve (AUC) to detect the sensitivity and specificity of each parameter. Mesopic vision evaluations were performed by contrast sensitivity and glare tests for each group. RESULTS: A total of 48 patients with clinical keratoconus in one eye and forme fruste keratoconus in the fellow eye and 72normal subjects were evaluated. In the clinical keratoconus eyes, the mean K, back difference elevation (BDE), pachymetric progression index maximum(PPI max), and multimetric D were significantly higher compared to the normal subjects, whereas the corneal pachymetry and Ambrósio relational thickness maximum (ART max) were significantly lower. In the forme fruste eyes, the ROC analysis showed that the AUC values of the mean K, thinnest pachymetry, ARTmax, BDE, D index, and PPI max were 0.82, 0.61, 0.88, 0. 67, and 0.64, respectively. The contrast sensitivity and glare tests were significantly affected in the forme fruste cases. CONCLUSION: In forme fruste keratoconus eyes, the ART max is considered a highly sensitive objective parameter. Contrast sensitivity and glare is an important subjective test, which is affected in forme fruste patients.

Visumax femtolasik versus Moria M2 microkeratome in mild to moderate myopia: efficacy, safety, predictability, aberrometric changes and flap thickness predictability.

INTRODUCTION: This is an interventional prospective clinical study which was conducted to evaluate the efficacy, safety, predictability, ocular aberrations, and flap thickness predictability of Visumax femtosecond laser (FSL) compared to Moria M2 microkeratome (MK) in mild to moderate myopia. METHODS: This study included 60 eyes who were divided into two groups. Thirty eyes in group (I) in which the flap was created with Visumax FSL, while in group II (30 eyes) the Moria M2 MK was used. Keratometric, refractive, and aberrometric measurements were compared preoperatively and 3 months postoperatively. The intraoperative subtraction pachymetry (the SP 100 Handy pachymeter (Tomey, Nagoya, Japan) was used for preoperative pachymetry and flap thickness measurement. RESULTS: No significant difference was found between the two groups in regards to postoperative manifest sphere, spherical equivalent, astigmatism, safety indices nor ocular aberrations. Twenty six eyes (86.6%) in group I and 23 eyes in group II (76.6%) were within ±0.5D of the intended correction and 23 eyes (76.6%) in group I and 15 eyes in group II (50%) were within ±0.25D of the intended correction. In group I, the mean postoperative actual flap thickness was 100.12 ± 16.1 µm (81 to 122 µm), while in group II, it was 104.6 ± 20.1 µm (62 to 155 µm). The difference was statistically significant (p = 0.001). CONCLUSIONS: Both Visumax and Moria M2 MK are safe and effective in treating myopia with no statistically significant difference in induction of ocular aberrations but with potential advantage for Visumax regarding predictability. More accurate flap thickness is achieved with Visumax femtolasik. TRIAL REGISTRATION: This study was retrospectively registered on 19/6/2017. Trial registration number NCT03193411 , clinicalTrials.gov .

Effects of Resveratrol, Lovastatin and the mTOR-Inhibitor RAD-001 on Insulin-Induced Genomic Damage In Vitro.

Diabetes mellitus (DM) is one of the major current health problems due to lifestyle changes. Before diagnosis and in the early years of disease, insulin blood levels are elevated. However, insulin generates low levels of reactive oxygen species (ROS) which are integral to the regulation of a variety of intracellular signaling pathways, but excess levels of insulin may also lead to DNA oxidation and DNA damage. Three pharmaceutical compounds, resveratrol, lovastatin and the mTOR-inhibitor RAD-001, were investigated due to their known beneficial effects. They showed protective properties against genotoxic damage and significantly reduced ROS after in vitro treatment of cultured cells with insulin. Therefore, the selected pharmaceuticals may be attractive candidates to be considered for support of DM therapy.

Efficacy of exercise on pelvic pain and posture associated with endometriosis: within subject design.

[Purpose] This study was carried out to determine the effect of an exercise program on pelvic pain and posture associated with endometriosis. [Subjects and Methods] This study was designed as repeated measures design that compared one group of 20 patients (age range 26-32 years) diagnosed by laparoscope as having mild or moderate endometriosis before, after 4 weeks, and after 8 weeks of exercise program. The exercise program parameters were based on the American College of Obstetricians and Gynecologists guidelines for exercise suitable for sedentary women. To assess the intensity of endometriosis pain, a present pain intensity scale was used. On the other hand, a raster stereography system was used to assess the posture. [Results] After 8 weeks of performing the exercise regimen, there was a statistically significant decrease in the patients' pain intensity and thoracic kyphosis angle program in compared with pre treatment. [Conclusion] Ultimately it was proven that eight weeks of an exercise program is very effective in decreasing pain and postural abnormalities associated with endometriosis.

Effect of Splenectomy on Coagulation and Platelet Function in Adult Liver Transplant Recipients Assessed With Rotational Thromboelastometry and Standard Coagulation Tests.

OBJECTIVES: Splenectomy during liver transplant can affect platelet function. In this study, our primary aim was to assess the perioperative platelet function by rotational thromboelastometry and the effects of splenectomy on platelet function. MATERIALS AND METHODS: We studied 40 consecutive liver transplant recipients with end-stage liver disease (50% as a result of hepatitis C). Patients with splenectomy were compared with patients without splenectomy (n = 20/group). Three platelet function parameters by rotational thromboelastometry were studied: platelet activation with arachidonic acid, platelet activation with adenosine diphosphate, and platelet activation with thrombin receptor-activating peptide 6. Patients were monitored perioperatively and until postoperative day 21. Heparin was infused for 2 days postoperatively (60-180 U/kg/day), followed by administration of subcutaneous low-molecular-weight heparin (40 mg/24 h) on postoperative days 2 and 3 and oral acetylsalicylic acid when platelet count was >50 × 103/µL. RESULTS: Liver disease contributed to low perioperative platelet count and function. Patients showed significant improvement by postoperative day 14 and day 21, particularly after splenectomy. Platelet count was significantly correlated with the 3 platelet function parameters by rotational thromboelastometry (P < .001). Acetyl salicylic acid was required earlier (postoperative day 3) for patients with splenectomy (8/20) but only affected the platelet function represented by platelet activation with arachidonic acid, whereas other platelet activation pathways were less affected. Patients received no transfusions of platelet units. CONCLUSIONS: End-stage liver disease significantly contributed to low platelet function and counts before transplant. Two weeks were required for recovery of patients posttransplant, with further enhancement by splenectomy. Some recipients showed recovery that exceeded the normal reference range, which warranted monitoring. Acetyl salicylic acid only affected 1 platelet activation receptor.

Dihydromyricetin protects against gentamicin-induced nephrotoxicity via upregulation of renal SIRT3 and PAX2.

AIM: Gentamicin-induced nephrotoxicity limits its widespread use as an effective antibacterial agent. Oxidative stress, inflammatory cytokines and apoptotic cell death are major participants in gentamicin-induced nephrotoxicity. We therefore, investigated whether dihydromyricetin (DHM), the antioxidant and anti-inflammatory flavonoid, could protect against the nephrotoxic effects of gentamicin. METHODS: Male Wistar rats administrated gentamicin (100 mg/kg/day, i.p.) for 8 days. DHM (400 mg/kg, p.o.) was concurrently given with gentamicin for 8 days. Control group received the vehicle of DHM and gentamicin. Histopathological examinations, biochemical measurements and immunohistochemical analyses were done at the end of the study. KEY FINDINGS: Treatment with DHM improved the gentamicin induced deterioration of renal functions; serum levels of urea, creatinine and cystatin-C as well as urinary levels of Kim-1 and NGAL, the sensitive indicators for early renal damage, were declined. Additionally, DHM abrogated gentamicin-induced changes in kidney morphology. These nephroprotective effects were possibly mediated via decreasing renal gentamicin buildup, activating the antioxidant enzymes GSH, SOD and CAT and decreasing lipid peroxidation and nitric oxide levels. Further, DHM suppressed renal inflammation and apoptotic cell death by decreasing the expression of nuclear factor-kappa B (NF-κB), TNF-alpha and caspase-3. These effects were correlated to the upregulation of renal SIRT3 expression. Also, DHM activated the regeneration and replacement of injured tubular cells with new ones via enhancing PAX2 expression. SIGNIFICANCE: DHM is a promising therapeutic target that could prevent acute renal injury induced by gentamicin and help renal tubular cells to recover through its antioxidant, anti-inflammatory and antiapoptotic properties.

Health and quality of life among women after participation in a CBPR-informed physical activity intervention: with a pandemic perspective.

The lack of culturally and contextually oriented interventions promoting physical activity (PA) has led to increased physical inactivity among women living in disadvantaged neighbourhoods in Sweden. In this study one such intervention informed by community-based participatory research (CBPR) has been evaluated among 34 women from a disadvantaged neighbourhood before and during COVID-19. Health-related quality of life (HRQOL), behavioural and biomedical outcomes were assessed directly prior and post-intervention, followed by evaluations at 6-months and 18-months follow-up during COVID-19. The results revealed that HRQOL, particularly psychological, social, and environmental health significantly increased post-intervention compared to prior to intervention but reversed back at 6-months follow-up. Perceived health satisfaction and environmental health increased at 18-months follow-up during COVID-19. Participation in PA improved post-intervention and at 6-months follow-up. Everyday activities and fruit and vegetable intake continued to increase through all timepoints. Systolic blood pressure significantly decreased post-intervention and 6-months follow-up; blood flow rate increased significantly at all timepoints. Overall, the findings underscores the potential effectiveness of CBPR approaches in promoting and sustaining healthy lifestyles, even during acute situations such as the COVID-19. It may even serve as a future model for promoting health and addressing health disparities in similar groups.

Thyroid gland dysfunction and vitamin D receptor gene polymorphism in keratoconus.

OBJECTIVES: To detect the serum level of thyroid hormones, vitamin D and vitamin D receptors (VDR) polymorphism in keratoconus (KC) patients and to identify the association between vitamin D deficiency and thyroid dysfunction in KC. METHODS: This cross sectional study included 177 KC patients with no thyroid disorders compared to 85 healthy controls with normal corneal tomography. Measurements of thyroid stimulating hormone (TSH), free triiodothyronine (FT3), free tetraiodothyronine (FT4) and serum 25-OH vitamin D were done using Enzyme linked immusoassay (ELISA test). VDR polymorphisms were tested including [Taq I (rs731236), Apa I (rs7975232) and Bsm I (rs1544410)] using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). RESULTS: An increase in frequency of thyroid disorders (P = 0.04), decrease in serum 25(OH) vitamin D level (P < 0.001), Taq 1 and tt genotype (P < 0.001) were significantly distributed in KC patients. A significantly higher serum 25(OH) vitamin D level was reported in TT genotype, while insufficient level was more common in Tt genotype (P < 0.001). A deficient serum 25(OH) vitamin D level was predominant in tt genotype (P < 0.001). A 95% confidence interval was in TSH (1.603, 2.946), FT4 (24.145, 77.06), hypothyroidism (1.062, 67.63), insufficient (2.936, 11.643) and deficient vitamin D (5.283, 28.704) and all were significant risk factors for KC with (P < 0.05). CONCLUSIONS: Both thyroid disorders and low vitamin D are potential factors for KC development. Studying VDR at the molecular level provides interesting avenues for future research toward the identification of new KC cases.

Dihydromyricetin Modulates Nrf2 and NF-κB Crosstalk to Alleviate Methotrexate-Induced Lung Toxicity.

BACKGROUND: Methotrexate (MTX) is an effective anticancer, anti-inflammatory, and immunomodulatory agent. However, it induces a serious pneumonitis that leads to irreversible fibrotic lung damage. This study addresses the protective role of the natural flavonoid dihydromyricetin (DHM) against MTX-induced pneumonitis via modulation of Nrf2/NF-κB signaling crosstalk. METHODS: Male Wistar rats were divided into 4 groups: control, which received the vehicle; MTX, which received a single MTX (40 mg/kg, i.p) at day 9 of the experiment; (MTX + DHM), which received oral DHM (300 mg/kg) for 14 days and methotrexate (40 mg/kg, i.p) on the 9th day; and DHM, which received DHM (300 mg/kg, p.o) for 14 days. RESULTS: Lung histopathological examination and scoring showed a decline in MTX-induced alveolar epithelial damage and decreased inflammatory cell infiltration by DHM treatment. Further, DHM significantly alleviated the oxidative stress by decreasing MDA while increasing GSH and SOD antioxidant levels. Additionally, DHM suppressed the pulmonary inflammation and fibrosis through decreasing levels of NF-κB, IL-1ß, and TGF-ß1 while promoting the expression of Nrf2, a positive regulator of antioxidant genes, and its downstream modulator, HO-1. CONCLUSION: This study identified DHM as a promising therapeutic target against MTX-induced pneumonitis via activation of Nrf2 antioxidant signaling while suppressing the NF-κB mediated inflammatory pathways.

Relation between Soluble CD14 Levels, Inflammation, Subclinical Atherosclerosis and Mortality in Hemodialysis Patients.

BACKGROUND AND AIM: Chronic kidney disease (CKD) is characterized by persistent lowgrade inflammation. Soluble CD14 (sCD14) is involved in many pathological conditions, including inflammation and atherosclerosis. The present study aimed to assess the relationship between sCD14 levels, subclinical atherosclerosis (SCA), inflammation and mortality in Egyptian hemodialysis (HD) patients. PATIENTS AND METHODS: The present longitudinal study included 62 HD patients. All patients were submitted to careful history taking, thorough clinical examination and laboratory assessment for high-sensitivity C-reactive protein (hsCRP) and sCD14. Carotid intima-media thickness (CIMT) was also assessed. Patients were followed for a maximum of 18 months. The primary outcome is patients' mortality. Data were statistically analyzed using standard descriptive, comparative, correlative and regression methods. RESULTS: The present study was conducted on 62 HD patients. They comprised 34 males and 28 females with an age of 54.6 ± 9.0 years. At the end of follow-up, 12 patients (19.4 %) died. It was shown that survivors had significantly lower hsCRP levels (104.2 ± 38.2 versus 134.1 ± 15.3 mg/dL, p < 0.001), lower sCD14 levels (32.7 ± 10.3 versus 47.4 ± 18.4 µg/mL, p = 0.02) and lower CIMT (1.32 ± 0.5 versus 1.5 ± 0.2 mm, p = 0.049). sCD14 levels were significantly correlated with hsCRP (r = 0.4, p = 0.001) and CIMT (r = 0.31, p = 0.013). Multivariate analysis identified HD duration [HR (95% CI): 1.02 (1.0-1.04), p = 0.021] and sCD14 levels [HR (95% CI): 1.06 (1.0-1.12), p = 0.026] as significant predictors of patients' survival. CONCLUSIONS: sCD14 levels in this cohort of HD patients are well-correlated with hsCRP levels and CIMT. In addition, they are significant predictors of patients' mortality.

Vanillin-Based Indolin-2-one Derivative Bearing a Pyridyl Moiety as a Promising Anti-Breast Cancer Agent via Anti-Estrogenic Activity.

The structure-based design introduced indoles as an essential motif in designing new selective estrogen receptor modulators employed for treating breast cancer. Therefore, here, a series of synthesized vanillin-substituted indolin-2-ones were screened against the NCI-60 cancer cell panel followed by in vivo, in vitro, and in silico studies. Physicochemical parameters were evaluated with HPLC and SwissADME tools. The compounds demonstrated promising anti-cancer activity for the MCF-7 breast cancer cell line (GI = 6-63%). The compound with the highest activity (6j) was selective for the MCF-7 breast cancer cell line (IC50 = 17.01 µM) with no effect on the MCF-12A normal breast cell line supported by real-time cell analysis. A morphological examination of the used cell lines confirmed a cytostatic effect of compound 6j. It inhibited both in vivo and in vitro estrogenic activity, triggering a 38% reduction in uterine weight induced by estrogen in an immature rat model and hindering 62% of ER-α receptors in in vitro settings. In silico molecular docking and molecular dynamics simulation studies supported the stability of the ER-α and compound 6j protein-ligand complex. Herein, we report that indolin-2-one derivative 6j is a promising lead compound for further pharmaceutical formulations as a potential anti-breast cancer drug.

Evaluating the Feasibility of Pro-Neurotensin and 25-Hydroxyvitamin D3 as Possible Indicators for Type 2 Diabetes Mellitus and Its Complications.

(1) Background: Type 2 diabetes mellitus (T2DM) and metabolic syndrome are associated with decreased vitamin D. In contrast, high pro-neurotensin (pro-NT) levels are linked with an increased risk of T2DM and cardiovascular disease. We aimed to determine the validity of pro-NT and 25-dihydroxy vitamin D3 levels as predictors for T2DM complications; (2) Methods: One hundred T2DM, and one hundred healthy volunteers participated in this case-control study. Their Pro-NT and 25-hydroxyvitamin D3 levels were evaluated using the ELISA technique; (3) Results: Pro-NT and 25 (OH) vitamin D3 have significant validity and accuracy in T2DM prediction, 84.5%, and 90.5%, respectively (p = 0.001). At a value of <29.5, 25-Hydroxy vitamin D3 showed 88% sensitivity and 93% specificity in predicting T2DM. At a value of >124 Pmol/L, Pro-NT showed 81% sensitivity and 88% specificity in predicting T2DM. At a value of 16.5, 25-Hydroxy vitamin D3 had 78.4% sensitivity and 68.3% specificity in predicting T2DM complications. At a value of >158 pmol/L, Pro-NT predicted T2DM complications with 67.6% sensitivity and 56.0% specificity; (4) Conclusions: 25 (OH) Vit D3 and Pro-NT could identify T2DM patients and predict T2DM complications. More extensive research is required to adequately validate this novel perspective with a large population study.